Copper-catalysed asymmetric conjugate addition of organometallic reagents to enones using S,O-ligands with a xylofuranose backbone

Article abstract of DOI:10.1016/S0957-4166(99)00546-7

The copper-catalysed enantioselective 1,4-addition reactions of diethylzinc to cyclohexenone and trimethylaluminium to E-non-3-en-2-one in the presence of thioether-alcohol ligands, which are easily prepared from D-(+)-xylose, resulted in e.e.s of up to 6

Full text of DOI:10.1016/S0957-4166(99)00546-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 871–877
Copper-catalysed asymmetric conjugate addition of
organometallic reagents to enones using S,O-ligands with a
xylofuranose backbone
Oscar Pàmies,a,∗ Gemma Net,a Aurora Ruiz,a,∗ Carmen Claver a and Simon Woodward b
aDepartament de Química Física i Inorgànica, Universitat Rovira i Virgili. Pl. Imperial Tàrraco 1, 43005 Tarragona, Spain
bSchool of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
Received 18 November 1999; accepted 26 November 1999
Abstract
The copper-catalysed enantioselective 1,4-addition reactions of diethylzinc to cyclohexenone and trimethyl-
aluminium to E-non-3-en-2-one in the presence of thioether-alcohol ligands, which are easily prepared from D-(+)-
xylose, resulted in e.e.s of up to 62% for cyclohexenone and 34% for E-non-3-en-2-one. © 2000 Elsevier Science
Ltd. All rights reserved.
1. Introduction
The enantioselective conjugate addition of organometallic reagents to α-β-unsaturated substrates,1 and
in particular, the addition of organocuprates to enones, is still to be of considerable synthetic interest.2
Excellent enantioselectivities have been obtained in the copper-catalysed Michael addition of Grignard
and diorganozinc reagents to enones and other α-β-unsaturated carbonyl compounds using phosphorus
ligands3–16 such as phosphorus amidites,3–10 oxazoline–phosphite11 and phosphite ligands12–14 (Fig.
1). However, one important limitation is that they exhibit high substrate specificity. Further efforts are
therefore required to design new chiral catalysts which can be applied more generally to different sizes
of cyclic and acyclic substrates.
Despite the early promising results obtained with thiolate ligands in the asymmetric copper-catalysed
Michael addition to enones,17–20 sulphur ligands have been less studied than their phosphorus coun-
terparts. As far as we know, thioether-based catalysts have never been applied in the copper-catalysed
1,4-addition of soft organometallics, e.g. ZnR2 and AlR3, to enones.
∗
Corresponding authors. Tel: (+34)-977559572; fax: (+34)-977559563; e-mail: pamies@quimica.urv.es,
aruiz@quimica.urv.es
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00546-7
tetasy 3181

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O. Pàmies et al. / Tetrahedron: Asymmetry 11 (2000) 871–877
Fig. 1.
In this paper we report the synthesis of a new thioether-alcohol ligand containing both a xylose and a
glucose backbone. We discuss the results of using this ligand and a family of thioether-alcohol ligands
with a xylofuranose backbone in the asymmetric copper addition of diethylzinc and trimethylaluminium
to 2-cyclohexenone and E-non-3-en-2-one, respectively (Scheme 1).
Scheme 1.
2. Results and discussion
2.1. Synthesis of ligand 1d
Thioether–alcohol 1d was synthesised from xylose via compound 2 (Scheme 2) using a slightly
modified literature method for 1a–c.21 The diol 2 was converted to the monotriflate 3 by the reaction
of a dichloromethane solution of 2 with triflic anhydride and pyridine. Treating compound 3 with a
stoichiometric amount of NaH and 1-thio-β-D-glucose tetraacetate at −78°C afforded ligand 1d. Higher
temperatures led to the elimination of the triflyl group as a secondary reaction.
Scheme 2. Synthesis of ligand 1d
2.2. Conjugate addition of 2-cyclohexenone
Ligands 1a–d were used in the copper-catalysed conjugate addition of diethylzinc to 2-cyclohexenone
(Table 1). The catalytic system was generated in situ by adding two equivalents of the corresponding
ligands to a solution of Cu(OTf)2 followed by addition of diethylzinc. In general, conversions and
regioselectivities in the 1,4-product were good for all ligands. There was no 1,2-product observed.

O. Pàmies et al. / Tetrahedron: Asymmetry 11 (2000) 871–877
873
Table 1
Catalytic conjugate addition reactions of ZnEt2 to 2-cyclohexenonea
The effect of the reaction temperature was studied for the system with ligand 1c. As reported for the
related Cu–diphosphite catalytic system22 the best enantiomeric excesses were obtained at 273 K (entry
1), and these decreased considerably when the reaction temperature was lowered (Fig. 2).
Increasing the catalyst loading increased the chemical yield but the 1,4-regio- and enantioselectivity
were not affected (entry 4 vs entry 1). Attempts to increase the catalytic activity at 273 K by adding a
Lewis acid promoter strongly suppressed both regio- and enantioselectivity (entry 5 vs entry 1).
The addition of diethylzinc proceeded with similar enantioselectivities in solvents of both lower and
higher polarity (entries 1–3). However, regioselectivities in favour of the 1,4-product were lower when
toluene, and especially THF, were used as solvents.
Changing the substituent of the thioether moiety produces an important effect on the rate and
stereoselectivities. Conversions are higher for the catalyst precursor containing the electron-rich 1b

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O. Pàmies et al. / Tetrahedron: Asymmetry 11 (2000) 871–877
Fig. 2. Variation of conversion and enantioselectivity vs temperature using ligand 1c
ligand (entry 9) while better enantioselectivities have been obtained with the catalyst precursor containing
ligand 1c (entry 1). The presence of a bulky substituent 1d has a detrimental effect on conversion and
enantioselectivity (entry 11). The formation of ligand-free copper aggregates could be responsible for
this.
2.3. Conjugate addition of E-non-3-en-2-one
Linear enones possessing only aliphatic substituents are a demanding substrate class for asymmetric
conjugate addition.23 The only highly enantioselective catalytic conjugate additions of this substrate class
are rhodium-catalysed.24 The enantioselective addition of alkyl groups has been successfully obtained
only recently.23
Table 2 shows the results of the thioether/copper-catalysed conjugate addition of trimethylaluminium
to E-non-3-en-2-one. There was no 1,2-product. It is noteworthy that better results have been obtained
using [Cu(MeCN)4]BF4 instead of Cu(OTF)2 as a catalyst precursor and when tetrahydrofuran was used
as a solvent.
As previously observed for 2-cyclohexenone, the introduction of sterically demanding groups in the
thioether moiety had a negative effect on selectivity, while at low temperature selectivities were better
than at 273 K (entries 3, 4 vs 5). This is in contrast with cyclohexenone addition, probably because of
the formation of different aggregates. Catalyst precursors containing the electron-rich ligands 1a and 1b
gave better conversions, while, as observed for 2-cyclohexenone, better enantioselectivities have been
obtained with the catalyst precursor that contained ligand 1c (entries 1, 2 vs 3).
In summary, chiral dithioether ligands are active in the enantioselective copper-catalysed 1,4-addition
of diethylzinc to cyclohexenone and produce enantiomeric excesses of up to 62% and have also shown
promising results (e.e.s of up to 34%) in the addition of trimethylaluminium to E-non-3-en-2-one. Further
investigation is in progress to delineate the scope and utility of the mixed thioether-alcohol ligands.
3. Experimental
3.1. General comments
All experiments were carried out under an argon atmosphere. All solvents were dried by standard pub-
lished methods and distilled prior to use. 1,2-O-Isopropylidenexylofuranose,26,27 1,2-O-isopropylidene-
5-O-trifluoromethanesulfanyl-α-D-(−)-xylofuranose21 and thioether-alcohol ligands 1a–c21 were prepa-
red by previously described methods. Elemental analyses were performed on a Carlo Erba EA-1108
1
instrument. H and 13C{1H} NMR spectra were recorded on a Varian Gemini 300 MHz spectrometer.
Chemical shifts are relative to SiMe4 (1H and 13C) as internal standard. All assignments in NMR spectra

O. Pàmies et al. / Tetrahedron: Asymmetry 11 (2000) 871–877
875
Table 2
Catalytic conjugate addition reactions of AlMe3 to E-non-3-en-2-onea
were determined by means of COSY and HETCOR spectra. Gas chromatographic analyses were run on
a Hewlett–Packard HP 5890A instrument equipped with a Hewlett–Packard HP 3396 series II integrator.
Optical rotations were measured at 20°C on a Perkin–Elmer 241 MC polarimeter. The specific rotations
are given in deg cm3 g−1 dm−1 units.
3.2. 1,2-O-Isopropylidene-5-(10-thio-20,30,40,60-tetra-O-acetyl-β-D-glucopyranosyl)-α-D-(−)-xylo-
furanose 1d
A solution of 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranose (1 g, 2.7 mmol) in THF (6 mL) was
added to a suspension of NaH (108 mg, 2.7 mmol) in THF (6 mL) at −78°C. After 30 min at −78°C, the
suspension was warmed to room temperature and a solution of 2 (0.8 g, 2.7 mmol) in THF (6 mL) was
added. After 90 min, water (50 mL) was added, the solvent was evaporated and the residue was extracted
with dichloromethane (3×50 mL). The extract was dried over magnesium sulfate and concentrated. The
residue was purified by column chromatography (hexane:ethyl acetate, 2:1) to give 1.01 g (70%) as a
white solid (decomposes at 130°C). Anal. calcd for C22H32O13S: C, 49.25; H, 6.01; S, 5.98. Found:
1
C, 49.88; H, 6.11; S, 5.79. H NMR (CDCl3): δ 1.28 (m, 3H, CMe), 1.47 (s, 3H, CMe), 1.99 (s, 3H,
OAc), 2.03 (s, 3H, OAc), 2.06 (s, 3H, OAc), 2.08 (s, 3H, OAc), 2.79 (m, 1H, OH), 2.82 (dd, 1H, H-5b,
2J5b-5a=12.9 Hz, 3J5b-4=10.2 Hz), 3.14 (dd, 1H, H-5a, 2J5a-5b=12.9 Hz, 3J5a-4=4.5 Hz), 3.72 (m, 1H, H-
50), 4.15 (m, 2H, H-60), 4.22 (m, 1H, H-4), 4.28 (m, 1H, H-3), 4.51 (d, 1H, H-2, 3J2-1=3.6 Hz), 04.58 (d,
3
0
0
1H, H-10, J1 -2 =10.2 Hz), 5.02 (t, 1H, H-4 , J=9.4 Hz), 5.12 (m, 1H, H-2 ), 5.21 (t, 1H, H-3 , J=9.4
0
0
Hz), 5.88 (d, 1H, H-1, 3J1-2=3.3Hz). 13C NMR (CDCl3): δ 20.4 (COMe), 26.0 (CMe), 26.6 (CMe), 27.2

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O. Pàmies et al. / Tetrahedron: Asymmetry 11 (2000) 871–877
(C-5), 62.1 (C-60), 68.2 (C-40), 69.8 (C-20), 73.5 (C-30), 74.0 (C-3), 75.9 (C-50), 79.8 (C-4), 83.9 (C-10),
84.9 (C-2), 104.9 (C-1), 113.2 (CMe), 169.5, 169.9, 170.2, 170.8 (CO). [α]D20=−20.6 (c=1, CHCl3).
3.3. Typical procedure for the catalytic conjugate addition of diethylzinc to 2-cyclohexenone
A solution of Cu(OTf)2 (9 mg, 0.025 mmol) and thioether (0.05 mmol) in dichloromethane (3 mL)
was stirred for 30 min at room temperature. After cooling to 273 K, diethylzinc (1 M sol. in hexanes,
3.5 mL, 3.5 mmol) was added. A solution of 2-cyclohexenone (0.24 mL, 2.5 mmol) and undecane as
GC internal standard (0.25 mL) in dichloromethane (3 mL) was then added. The reaction was monitored
by GC. After 1 h the reaction was quenched with HCl (2 M) and filtered twice through flash silica. The
chemical yield and enantiomeric excesses were obtained by GC using a Lipodex-A column.
3.4. Typical procedure for the catalytic conjugate addition of trimethylaluminium to E-non-3-en-2-one
Trimethylaluminium solution (1 M sol., 100 µL, 0.1 mmol) was added to a THF solution (1 mL)
containing thioether (0.1 mmol) and [Cu(MeCN)4]BF4 (15.7 mg, 0.05 mmol) at 253 K. After 1 min
the trimethylaluminium (1 M sol., 0.75 mL, 0.75 mmol) and enone (0.6 M sol. in THF, 0.75 mL, 0.5
mmol) were introduced sequentially and in a dropwise manner over 20 min. After 20 min the reaction
was quenched with HCl (2 M) and undecane as GC internal standard (50 µL) was added. The organic
layer was filtered twice through flash silica. The chemical yield and e.e.s were obtained by GC using an
oktakis-(6-O-methyl-2,3-di-O-pentyl)-γ-cyclodextrin column.
Acknowledgements
We thank the Spanish Ministerio de Educación y Cultura and the Generalitat de Catalunya (CIRIT) for
financial support (PB97-0407-CO5-01) and the Generalitat de Catalunya (CIRIT) for awarding a research
grant (to O.P.). We thank the COST-D12 programme for support.
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